This invention relates to new compositions of N-acetonylbenzamide fungicides, methods of preparing the N-acetonylbenzamides, and their use as fungicides.
N-acetonylbenzamide fungicides are known, see, e. g., U. S. Pat. Nos. 5,254,584 and 5,304,572. One advantage of these known fungicides is that they have high fungicidal activity. Such compounds are particularly advantageous because their high activity allows them to be used at low application rates. However, there is always a need for fungicidal compounds of even higher activity. This results in lower use rates and, therefore, less environmental contamination.
We have discovered that with certain N-acetonylbenzamide fungicides which contain an assymetric carbon atom, the fungicidal activity results primarily from one enantiomer. Thus, fungicidal compositions containing only the active enantiomer provide higher fungicidal activity than compositions containing both enantiomers, when used at the same use rate.
This invention provides compositions, comprising:
a. a compound of formula I, with the stereochemistry depicted: 
wherein:
1. A is selected from N and C-R5;
2. R1 and R2 are different and are independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and halo(C1-C6)alkyl and R2 is stereochemically larger than R1;
3. R3, R4, and R5 are independently selected from H, halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, halo(C1-C6)alkyl, (Cl-C6)alkoxy, halo(C1-C6)alkoxy, cyano, nitro, xe2x80x94CR6=NOR7, xe2x80x94NR8R9, xe2x80x94CONR10R11, and xe2x80x94NHxe2x80x94COxe2x80x94OR12 wherein R6 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl, R7 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C1-C6)alkylcarbonyl, R8 and R9 are independently selected from H, (C1-C6)alkyl, and (C1-C6)alkylcarbonyl, R10and R11 are independently selected from H and (C1-C6)alkyl; and R12 is selected from H, (C1 -C6)alkyl, (C2-C6) alkenyl, and (C2-C6)alkynyl; and
4. X, Y, and Z are independently selected from H, halo, cyano, thiocyano, isothiocyano, and (C1-C4)alkylsulfonyloxy; provided that X, Y, and Z are not all H; and
b. an agronomically acceptable carrier;
wherein the composition is predominantly free of the compound of formula I wherein R1 is stereochemically larger than R2;.
The term xe2x80x9chaloxe2x80x9d means chloro, fluoro, bromo, or iodo. The terms xe2x80x9calkylxe2x80x9d and xe2x80x9calkenylxe2x80x9d include straight-chain, branched-chain, and cycloalkyl and alkenyl groups. The term xe2x80x9calkynylxe2x80x9d includes straight-chain and branched-chain alkynyl groups. The term xe2x80x9calkoxyxe2x80x9d includes as the alkyl portion straight-chain, branched-chain, and cyclic alkyl and alkenyl groups. The term xe2x80x9chaloxe2x80x9d preceeding any one of alkyl, alkenyl, alkynyl, or alkoxy means that one or more of the hydrogens of the group is substituted with a halogen.
The term xe2x80x9cstereochemically largerxe2x80x9d means the group in question is more space-filling than the group to which it is being compared. When the R1 and R2 groups in formula I contain only carbon and hydrogen atoms, since R2 is the stereochemically larger group, the stereochemistry about the atom to which the R1 and R2 groups are attached will take on an xe2x80x9cSxe2x80x9d configuration. That is, the compound of formula I is designated as the S enantiomer. Throughout this application, the term xe2x80x9cS enantiomerxe2x80x9d means that the four groups on the carbon to which R1 and R2 are attached, when ranked according to the set of sequence rules of the Cahn-Ingold-Prelog system (Angew. Chem. Int. Ed. Engl. 5, 385-415(1966)), define the carbon as having an S configuration. The term xe2x80x9cR enantiomerxe2x80x9d means that the four groups form an R configuration. The term xe2x80x9cpredominantly freexe2x80x9d means that the ratio of enantiomers is greater than 3:1, preferably greater than 5:1, more preferably greater than 10:1, and most preferably greater than 100:1.
Because of their high fungicidal activity preferred compounds are those of formula I wherein: R3 is selected from halo, cyano, nitro, and xe2x80x94CH=NOCH3; R4 is selected from H, halo, cyano, (C1-C6)alkyl, 13 NHxe2x80x94COxe2x80x94OR12,and xe2x80x94NR10R11; R5 is selected from halo, cyano, and (C1-C6)alkyl; R1 and R2 are independently selected from (C1-C6)alkyl; X and Y are H; and Z is chloro.
Because of their outstanding fungicidal activity and selectivity the most preferred compounds of formula I are those wherein: R3 is selected from chloro, bromo, CN, and xe2x80x94CH=NOCH3; R4 is selected from H, xe2x80x94NH2, CN, and xe2x80x94CH3; R5 is selected from chloro, bromo, CN, and xe2x80x94CH3; R1 is methyl; R2 is ethyl; X and Y are H; and Z is chloro.
This invention also provides fungicidal compounds of formula I.
In addition, this invention provides a process for preparing compounds of formula I, comprising the steps of:
a. reacting a protonated amino acid ester of the formula: 
wherein R1 and R2 are different and are independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and halo(C1-C6)alkyl and R2 is stereochemically larger than R1,and R is selected from (C1-C6)alkyl, with an acyl chloride of the formula: 
wherein A is selected from N and C-R5 and R3, R4, and R5 are independently selected from H, halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, halo(C1-C6)alkyl, (C 1-C6)alkoxy, halo(C1-C6)alkoxy, cyano, nitro, xe2x80x94CR6=NOR7, xe2x80x94NR8R9, xe2x80x94CONR10R11, and xe2x80x94NH-CO-OR12 wherein R6 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl, R7 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C1-C6)alkylcarbonyl, R8 and R9 are independently selected from H, (C1-C6)alkyl, and (C1-C6)alkylcarbonyl, R10and R11are independently selected from H and (C1-C6)alkyl; and R12 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; to produce a benzamide-ester of the formula: 
b. hydrolyzing the ester moiety of the benzamide-ester to produce a benzamide-acid of the formula: 
c. cyclizing the benzamide-acid to produce an oxazolinone of the formula: 
d. forming the c ompound of formula I by ring opening the oxazolinone.
The protonated amino acid ester may be prepared using standard esterification procedures such as treatment of the corresponding amino acid with an alcohol under acidic conditions. We have found that methanol is the preferred alcohol because of the ease of removal of a methyl group during the hydrolyzing step.
In a similar manner, the hydrolyzing step is conducted using standard conditions. Base catalyzed hydrolysis using sodium hydroxide as the base is preferred. The only limitations to the reaction conditions used in the hydrolyzing step are that the conditions must be sufficiently selective so that the ester bond is hydrolyzed but the amide bond is not. Strong base catalysts must be avoided when R1 or R2 is hydrogen to eliminate side reactions resulting from abstraction of the hydrogens.
The oxazolinone is produced in the cyclization step by dehydration of the benzamide-acid. Such dehydrations may be conducted using a variety of dehydrating agents such as acetic anhydride at elevated temperatures (90xc2x0-100xc2x0 C.) phosphorous oxychloride, phosphorous pentachloride, and ethyl hloroformate/triethylamine. Mild dehydrating agents such as acetic anhydride are preferred because they are easily removed and side reactions are avoided.
Ring opening of the oxazolinone to form the compound of formula I may be conducted in a single or in multiple steps. An example of a single step ring opening is treating the oxazolinone with chloromethyllithium which produces the compound of formula I wherein X and Y are H and Z is Cl. An example of a multiple step ring opening is treating the oxazolinone first with methyllithium to form the compound of formula I wherein X, Y, and Z are all H, chlorinating the ketone to produce a mixture of compounds of formula I wherein one or two of X, Y, and Z are Cl and the remaining are H, followed by selective removal of one chlorine atom from any compound in which two of X, Y, and Z are Cl to give a compound of formula I wherein two of X, Y, and Z are H and the remaining is Cl. The removal of one chlorine atom may be accomplished by hydrogenation of the dichloro compound in the presence of a catalyst such as palladium.
This same process may also be employed to produce a racemic mixture of R and S isomers of the compound of formula I by utilizing a racemic mixture of the R and S isomers of the protonated amino acid ester in the first step.
Compositions containing compounds of formula I and an agronomically acceptable carrier are useful in controlling a broad spectrum of phytopathogenic fungi such as those of the classes Oomycetes, Deuteromycetes, and Ascomycetes.
The compositions and compounds of the present invention (compounds of formula I) are useful for the control of phytopathogenic fungi on crops and may be used as seed protectants, soil fungicides and/or foliar fungicides. As a seed protectant, a compound of the present invention is coated on seed at a dosage rate of about 5 grams (g) compound per 50 kilograms (kg) seed to about 250 g compound per 50 kg seed. As a soil fungicide, a compound of the present invention can be incorporated in the soil or applied to the surface of the soil at a dosage rate of about 0.25 kg compound per hectare to about 10 kg compound per hectare and preferably at a rate of about 0.5 kg compound per hectare to about 2.5 kg compound per hectare.
The compositions and compounds of the present invention can be applied to plant foliage as fungicidal sprays by methods commonly employed, such as conventional high-gallonage hydraulic sprays, low-gallonage sprays, air-blast, aerial sprays and dusts. While the dilution and rate of application will depend upon the type of equipment employed, the method and frequency of application desired and diseases to be controlled, the effective amount is typically from about 0.005 kg compound per hectare to about 1.0 kg compound per hectare, preferably from about 0.05 kg compound per hectare to about 0.5 kg compound per hectare and more preferably from about 0.0625 kg compound per hectare to about 0.25 kg compound per hectare.
For the above disclosed purposes these compounds can be used in the pure form, also known as technical in the art, as prepared, or as solutions or as formulations. The compounds are usually provided with a carrier or are formulated so as to render them suitable for subsequent use as fungicides. For example, the compounds can be formulated as wettable powders, dry powders, emulsifiable concentrates, dusts, granular formulations, aerosols, or flowable emulsion concentrates. In such formulations, the compounds are extended with a liquid or solid carrier and, when dried, suitable surfactants are incorporated.
It is usually desirable, particularly in the case of foliar spray formulations, to include adjuvants, such as wetting agents, spreading agents, dispersing agents, stickers, adhesives and the like in accordance with agricultural practices. Such adjuvants commonly used in the art can be found in McCutcheon""s Emulsifiers and Detergents, McCutcheon""s Emulsifiers and Detergents/Functional Materials and McCutcheon""s Functional Materials all published annually by McCutcheon Division of MC Publishing Company (N.J.).
In general, the compounds utilized in this invention can be dissolved in appropriate solvents such as acetone, methanol, ethanol, dimethylformamide or dimethyl sulfoxide and such solutions extended with water. The concentrations of the solution can vary from 1% to 90% with a preferred range being 5% to 50%.
For the preparation of emulsifiable concentrates, the compounds used in the invention can be dissolved in suitable organic solvents or a mixture of solvents, together with an emulsifying agent which permits dispersion of the fungicide in water. The concentration of the active ingredient in emulsifiable concentrates is usually 10% to 90% and in flowable emulsion concentrates, this can be as high as 75%. Wettable powders suitable for spraying, can be prepared by admixing the compound with a finely divided solid or mixture of solids, such as clays, inorganic silicates, inorganic carbonates, and silicas and incorporating wetting agents, sticking agents, and/or dispersing agents in such mixtures. The concentration of active ingredients in such formulations is usually in the range of 20% to 98%, preferably 40% to 75%.
Dusts are prepared by mixing the compounds of the present invention salts and complexes thereof with finely divided inert solids which can be organic or inorganic in nature. Inert materials useful for this purpose include botanical flours, silicas, silicates, carbonates and clays. One convenient method of preparing a dust is to dilute a wettable powder with a finely divided carrier. Dust concentrations containing 20% to 80% of the active ingredient are commonly made and are subsequently diluted to 1% to 10% use concentration.
The compounds of the present invention can also be utilized in combination with other fungicides such as, for example, those disclosed in U. S. Pat. No. 5,304,572 (column 3, line 30 to column 4, line 52) as well as acylalanines such as , furalaxyl, cyprofuram, ofurace, benalaxyl, and oxadixyl;, fluazinam, flumetover, phenylbenzamide derivatives such as those disclosed in EP 578586 A1, amino acid derivatives such as valine derivatives disclosed in EP 550788 A1, methoxyacrylates such as methyl (E)-2-(2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl)-3-methoxyacrylate; benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester: propamocarb; imazalil; carbendazim; myclobutanil; fenbuconazole; tridemorph; pyrazophos; fenarimol; fenpiclonil; pyrimethanil; and tin fungicides. Those skilled in the art will recognize that mixtures of the respective compositions and compounds of the present invention with other fungicidally active compounds may provide advantages such as a broader spectrum of antifungal activity than the respective compositions and compounds of the present invention alone.
In a similar manner, the compositions and compounds of this invention may be applied in combination with one or more insecticides such as those disclosed in U. S. Pat. No. 5,075,471 (columns 14 and 15). Again, those skilled in the art will recognize that mixtures of the respective compositions and compounds of the present invention with insecticidally active compounds may provide advantages such as fewer total applications than if the fungicides and insecticides are applied separately.
The following examples describe in detail some of the embodiments of this invention.